6OSV

Potent and Selective Antitumor Antibody Targeting a Membrane-Proximal Epitope of ROR2

6OSV の概要

• エントリーDOI: 10.2210/pdb6osv/pdb
• 分子名称: Antibody light chain variable region, Tyrosine-protein kinase transmembrane receptor ROR2, Antibody heavy chain variable region, ... (4 entities in total)
• 機能のキーワード: single chain fv, scfv, antibody, ror2, kringle domain, receptor tyrosine kinase-like orphan receptor, phage display, immune system, immune sytem-transferase complex, immune sytem/transferase
• 由来する生物種: Oryctolagus cuniculus; 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 36110.97

構造登録者

Park, H.,Rader, C. (登録日: 2019-05-02, 公開日: 2020-04-01, 最終更新日: 2020-05-13)

主引用文献

Goydel, R.S.,Weber, J.,Peng, H.,Qi, J.,Soden, J.,Freeth, J.,Park, H.,Rader, C.
Affinity maturation, humanization, and co-crystallization of a rabbit anti-human ROR2 monoclonal antibody for therapeutic applications.
J.Biol.Chem., 295:5995-6006, 2020

PubMed Abstract: Antibodies are widely used as cancer therapeutics, but their current use is limited by the low number of antigens restricted to cancer cells. A receptor tyrosine kinase, receptor tyrosine kinase-like orphan receptor 2 (ROR2), is normally expressed only during embryogenesis and is tightly down-regulated in postnatal healthy tissues. However, it is up-regulated in a diverse set of hematologic and solid malignancies, thus ROR2 represents a candidate antigen for antibody-based cancer therapy. Here we describe the affinity maturation and humanization of a rabbit mAb that binds human and mouse ROR2 but not human ROR1 or other human cell-surface antigens. Co-crystallization of the parental rabbit mAb in complex with the human ROR2 kringle domain (hROR2-Kr) guided affinity maturation by heavy-chain complementarity-determining region 3 (HCDR3)-focused mutagenesis and selection. The affinity-matured rabbit mAb was then humanized by complementarity-determining region (CDR) grafting and framework fine tuning and again co-crystallized with hROR2-Kr. We show that the affinity-matured and humanized mAb retains strong affinity and specificity to ROR2 and, following conversion to a T cell-engaging bispecific antibody, has potent cytotoxicity toward ROR2-expressing cells. We anticipate that this humanized affinity-matured mAb will find application for antibody-based cancer therapy of ROR2-expressing neoplasms.

PubMed: 32193207
DOI: 10.1074/jbc.RA120.012791

実験手法

X-RAY DIFFRACTION (1.34 Å)